PROJECT SUMMARY Patients with end stage kidney disease on dialysis have deranged mineral metabolism, including often severe changes in calcium, phosphorus, parathyroid hormone and the phosphorus-regulatory hormone fibroblast growth factor 23. Pre-clinical studies strongly suggest that these mineral metabolism abnormalities may directly increase risk of common morbidities in this group including cardiovascular and bone disease. These potential effects in pre-clinical studies are supported by observational studies in patients linking mineral metabolism abnormalities with morbidity and mortality. Although treatment of mineral metabolism derangements is widespread in practice, there are no definitive trials demonstrating the best approaches to prevent common adverse outcomes in patients on dialysis such as accelerated mortality, cardiovascular disease and frequent hospital admissions. This application will utilize clinical practice data as well as patient and provider engagement to design needed trials and overcome prior barriers to trial success such as high rates of mineral metabolism treatment discontinuation and change. Because (1) multiple classes of pharmacologic agents are available to treat mineral metabolism abnormalities; and, (2) guidelines advocate broad ranges for biochemical parameters, such as phosphorus and parathyroid hormone, providers have many choices for their overall approach to mineral metabolism treatment and demonstrate substantial variation in approaches. This proposal will leverage real-world practice data derived from detailed medical records and linked administrative claims in a large population of patients treated with in-center hemodialysis to understand alternative treatment strategies and compare their outcomes. Aim 1 will define common treatment strategies that incorporate different pharmacologic agent combinations, doses and mineral metabolite target values (i.e., integrated strategies), and identify predictors of different prescribing practices in this area using discrete choice models. Aim 2 will evaluate the prospective association of integrated treatment strategies with adverse clinical outcomes, including mortality, cardiovascular disease events, fracture, hospitalization and health-related quality of life. Unique data elements, such as frequently updated medication and clinical data and facility clustering are well-suited to marginal structural modeling and instrumental variable methods to better account for potential confounding. In Aim 3, focus groups and directed interviews with patients and dialysis care providers will be used to deeply evaluate underlying reasons for frequent discontinuation and change of the treatment strategy that plagued prior trials. Ultimately, these studies will identify alternative strategies that are practical in real-world settings, associated with the most optimal clinical outcomes and sustainable through optimized care delivery, thereby solidifying the evidence-base for practice in this pervasive aspect of dialysis care. Additionally, results will select intervention and comparator strategies, from among many possibilities, that may be most effective and sustainable for further testing in definitive trials.